Interleukin-19 Abrogates Experimental Autoimmune Encephalomyelitis by Attenuating Antigen-Presenting Cell Activation.

Hiroshi Horiuchi,Yasu-Taka Azuma,Akio Suzumura,Keita Takahashi,Shijie Jin,Hideyuki Takeuchi,Hiroyasu Komiya,Bijay Parajuli,Yuki Ogawa,Fumiaki Tanaka

doi:10.3389/fimmu.2021.615898

Hiroshi Horiuchi, Yasu-Taka Azuma + Show 8 more

Open Access

https://doi.org/10.3389/fimmu.2021.615898

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Abstract

Interleukin-19 (IL-19) acts as a negative-feedback regulator to limit proinflammatory response of macrophages and microglia in autocrine/paracrine manners in various inflammatory diseases. Multiple sclerosis (MS) is a major neuroinflammatory disease in the central nervous system (CNS), but it remains uncertain how IL-19 contributes to MS pathogenesis. Here, we demonstrate that IL-19 deficiency aggravates experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by promoting IL-17-producing helper T cell (Th17 cell) infiltration into the CNS. In addition, IL-19-deficient splenic macrophages expressed elevated levels of major histocompatibility complex (MHC) class II, co-stimulatory molecules, and Th17 cell differentiation-associated cytokines such as IL-1β, IL-6, IL-23, TGF-β1, and TNF-α. These observations indicated that IL-19 plays a critical role in suppression of MS pathogenesis by inhibiting macrophage antigen presentation, Th17 cell expansion, and subsequent inflammatory responses. Furthermore, treatment with IL-19 significantly abrogated EAE. Our data suggest that IL-19 could provide significant therapeutic benefits in patients with MS.

Highlights

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, are major autoimmune demyelinating diseases of the central nervous system (CNS) [1, 2]
These results suggest that endogenous IL-19 serves as a negative regulator of EAE pathogenesis at both the induction and effector phases
We revealed that IL-19 deficiency significantly upregulated mRNA levels of these Th17 cell differentiation-associated cytokines in macrophages, but not in dendritic cell (DC) (Figure 4 and Supplementary Figure 3), these protein levels have not been evaluated in this study

Summary

INTRODUCTION

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, are major autoimmune demyelinating diseases of the central nervous system (CNS) [1, 2]. Various types of immune cells and soluble mediators contribute to the complex mechanisms underlying the onset and progression of both MS and EAE, and recent studies have shown that type 1 helper T (Th1) cells and interleukin-17-producing helper T (Th17) cells play pivotal roles in their pathogenesis [3,4,5] In these diseases, autoreactive Th17 cells primed in the lymph nodes infiltrate the CNS and activate microglia/macrophages that induce inflammatory demyelination and subsequent neuronal damage, resulting in a wide range of clinical features, including sensory and motor paralysis, blindness, pain, incontinence, and dementia [1, 2]. Our findings suggest that IL-19 may provide significant therapeutic benefits for treating MS

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